A djuvant immune checkpoint inhibition (CPI) and BRAF/ MEK-targeted therapies after therapeutic lymph node dissection (TLND) have improved relapse-free survival (RFS) in patients with clinical stage III nodal melanoma. Despite these improvements, approximately 40-50% of patients have a relapse within 3-5 years after TLND 1-3 . Preclinical and early clinical trial data suggest that neoadjuvant CPI leads to superior anti-tumor immunity and survival benefit compared to adjuvant CPI 4,5 . Similarly to stage IV melanoma, the combination of anti-CLTA-4 and anti-PD-1 appears to be superior to anti-PD-1 monotherapy in the neoadjuvant setting 6,7 . Previous clinical trials (OpACIN (NCT02437279) and OpACIN-neo (NCT02977052)) testing neoadjuvant ipilimumab (anti-CTLA-4) plus nivolumab (anti-PD-1) in stage III melanoma demonstrated high pathologic response rates (pRRs; 74-78%) and a strong association between pathologic response and RFS, with 94-100% of responding patients remaining free of relapse at 2 years 5,7-9 . Similarly, long-term benefit was observed upon complete response to CPI in stage IV melanoma, even after cessation of CPI [10][11][12] .The association between response and survival; the observed ongoing responses after cessation of therapy in stage IV melanoma; and the substantial morbidity from TLND [13][14][15][16] that impairs

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10002 Background: OpACIN-neo tested 3 dosing schemes of neoadjuvant (neoadj) IPI+NIVO and identified 2 cycles of IPI 1mg/kg + NIVO 3mg/kg (I1N3) as the most favorable with a pathologic (path) response rate (pRR) of 77% and 20% grade 3-4 irAEs. After 17.6 months median FU, 1/64 (2%) patients (pts) with path response vs 13/21 (62%) of the non-responders ( > 50% viable tumor cells; pNR) had relapsed. We hypothesized that therapeutic lymph node dissection (TLND) could be omitted in pts achieving a complete or near-complete path response (≤10% viable tumor cells; major path response, MPR) in the index node (largest LN metastasis: ILN), whereas additional adjuvant (adj) therapy might improve the outcome of pNR pts. Methods: PRADO is an extension cohort of the multi-center phase 2 OpACIN-neo study that aims to confirm the pRR and safety of neoadj I1N3 and to test response-driven subsequent therapy. Pts with RECIST 1.1 measurable clinical stage III melanoma were included to receive 2 cycles of neoadj I1N3 after marker placement in the ILN. ILN resection was planned at wk 6. Pts that achieved MPR in the ILN did not undergo TLND; pts with pPR ( > 10 – ≤50% viable tumor cells) underwent TLND; and pts with pNR underwent TLND and received adj NIVO or targeted therapy (TT) for 52 wks +/- radiotherapy (RT). Primary endpoints were pRR in the ILN and 24-month RFS. Estimated toxicity rates at wk 12 were calculated using a Kaplan Meier based method. Results: Between Nov 16, 2018 and Jan 3, 2020, 99 of 114 screened pts were eligible and enrolled. So far, 86 pts had ≥12 wks FU. 70/99 pts achieved a path response in the ILN (pRR 71%, 95% CI 61% - 79%); 60 (61%) had MPR. TLND was omitted in 58 (97%) of the MPR pts. There were 28 non-responders; 7 developed distant metastasis before ILN resection. To date, 8 of the 21 pNR pts had adj NIVO, 7 had adj TT and 7 had adj RT. The estimated grade 3-4 irAE rate at wk 12 was 24%. Due to toxicity, 10 pts (10%) received only 1 cycle I1N3 and in 3 pts ILN resection was not performed: 2 of these pts underwent TLND at wk 9 and one pt was not evaluated for path response. At data cutoff, the surgery-related grade 1,2 and 3 AE rates were 29%, 10% and 0% in pts who underwent ILN resection only vs 21%, 30% and 9% in pts who underwent subsequent TLND (p = 0.004). At ASCO 2020 all pts will have reached ≥12 wks FU. Conclusions: Neoadj I1N3 treatment induced a high pRR with tolerable toxicity. TLND was omitted in a major subset of pts, reducing surgical morbidity. Longer FU is needed to report safety and RFS when TLND is omitted in MPR pts. Clinical trial information: NCT02977052.

ImportanceManagement of checkpoint inhibitor–induced immune-related adverse events (irAEs) is primarily based on expert opinion. Recent studies have suggested detrimental effects of anti–tumor necrosis factor on checkpoint-inhibitor efficacy.ObjectiveTo determine the association of toxic effect management with progression-free survival (PFS), overall survival (OS), and melanoma-specific survival (MSS) in patients with advanced melanoma treated with first-line ipilimumab-nivolumab combination therapy.Design, Setting, and ParticipantsThis population-based, multicenter cohort study included patients with advanced melanoma experiencing grade 3 and higher irAEs after treatment with first-line ipilimumab and nivolumab between 2015 and 2021. Data were collected from the Dutch Melanoma Treatment Registry. Median follow-up was 23.6 months.Main Outcomes and MeasuresThe PFS, OS, and MSS were analyzed according to toxic effect management regimen. Cox proportional hazard regression was used to assess factors associated with PFS and OS.ResultsOf 771 patients treated with ipilimumab and nivolumab, 350 patients (median [IQR] age, 60.0 [51.0-68.0] years; 206 [58.9%] male) were treated with immunosuppression for severe irAEs. Of these patients, 235 received steroids alone, and 115 received steroids with second-line immunosuppressants. Colitis and hepatitis were the most frequently reported types of toxic effects. Except for type of toxic effect, no statistically significant differences existed at baseline. Median PFS was statistically significantly longer for patients treated with steroids alone compared with patients treated with steroids plus second-line immunosuppressants (11.3 [95% CI, 9.6-19.6] months vs 5.4 [95% CI, 4.5-12.4] months; P = .01). Median OS was also statistically significantly longer for the group receiving steroids alone compared with those receiving steroids plus second-line immunosuppressants (46.1 months [95% CI, 39.0 months-not reached (NR)] vs 22.5 months [95% CI, 36.5 months-NR]; P = .04). Median MSS was also better in the group receiving steroids alone compared with the group receiving steroids plus second-line immunosuppressants (NR [95% CI, 46.1 months-NR] vs 28.8 months [95% CI, 20.5 months-NR]; P = .006). After adjustment for potential confounders, patients treated with steroids plus second-line immunosuppressants showed a trend toward a higher risk of progression (adjusted hazard ratio, 1.40 [95% CI, 1.00-1.97]; P = .05) and had a higher risk of death (adjusted hazard ratio, 1.54 [95% CI, 1.03-2.30]; P = .04) compared with those receiving steroids alone.Conclusions and RelevanceIn this cohort study, second-line immunosuppression for irAEs was associated with impaired PFS, OS, and MSS in patients with advanced melanoma treated with first-line ipilimumab and nivolumab. These findings stress the importance of assessing the effects of differential irAE management strategies, not only in patients with melanoma but also tumor types.